Synthesis of aryl ethers

ABSTRACT

A method for preparing an aryl ether compound is provided in which an alcohol is reacted with an aromatic compound in the presence of a base, and a transition metal catalyst selected from the group consisting of platinum and nickel to form an aryl ether. The aromatic compound comprises an activated substituent, X, said activated substituent being a moiety such that its conjugate acid HX has a pKa of less than 5.0. The catalyst is preferably a soluble palladium complex in the presence of supporting ligands.

GOVERNMENT SUPPORT

This invention was made with government support under Grant Number9412982-CHE awarded by the National Science Foundation. The governmenthas certain rights in the invention.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.08/728,449, filed Oct. 10, 1996, which issued as U.S. Pat. No. 5,847,166on Dec. 8, 1998.

BACKGROUND OF THE INVENTION

The present invention relates to improved methods for preparing arylethers which are useful intermediates and end products in pharmaceuticaland agricultural applications.

It has been recently reported that aryl bromides react with simpleprimary and secondary amines in the presence of a palladium catalyst,supporting ligands and Na(OtBu) (base) to form the correspondingarylamine in good yields. See, Guram et al. Angew. Chem. 34(12):1348(1995).

Despite the recent successes with palladium-catalyzed cross-couplingreactions of Ar--X (X=Br) with amines, comparable coupling of arylhalides with alcohols remains elusive, and this in spite of its obviousutility in organic synthesis. Aryl ethers, including oxygenheterocycles, are prominent in a large number of pharmacologicallyimportant molecules and are found in numerous secondary metabolites.

Existing methods for the conversion of Ar--X to aryl ethers oftenrequire harsh or restrictive reaction conditions and/or the presence ofactivating groups on the arene ring. For example, the Cu(I)-catalyzedsyntheses of aryl and vinyl ethers commonly require large amounts offreshly prepared sodium alkoxides and/or large excess of thecorresponding alcohol in order to achieve reasonable yields from thecorresponding aryl halides and vinyl halides. See, Keegstra et al.Tetrahedron 48(17):3633 (1992).

Cramer and Coulson also reported limited success with theNi(II)-catalyzed synthesis of diphenyl ether using sodium phenolate atreaction temperatures greater than 200° C. See, J. Org. Chem.40(16):2267 (1975). Christau and Desmurs describe the nickel-catalyzedreactions of alcohols with aryl bromides in the presence of a base. Goodyields (ca. 80%) were reported only for reactions with primary alcoholswith 7 mol % nickel catalyst at 125° C . Ind. Chem Libr. 7:240 (1995).Christau and Desmurs also reported that synthesis of aryl ethers waspossible only for primary and secondary alcohols. Houghton and Voylereported the Rh(IIl)-catalyzed cyclization of3-(2-fluorophenyl)propanols to chromans activated by π-bonding to themetal center; however, the reaction required very high rhodium catalystloading (17 mol %). See, J. Chem. Soc. Perkin Trans. I, 925 (1984).

Ether formation has been reported as a minor side product in thepalladium-catalyzed carbonylation reactions of highly activated aromaticcompound such as α-substituted quinolines. Because of the highlyreactive nature of the α-site, it is possible that the reaction proceedsby direct nucleophilic substitution, without promotion or catalysis bythe palladium metal center. See, Cacchi et al. Tet. Lett. 27(33):3931(1986).

Thus there remains a need for an effective method of preparing a widerange of aryl ethers under mild conditions and in high yields. There isa further need for an efficient catalytic system with high efficienciesand turnover number for the synthesis of aryl ethers. In addition, therestill remains a need for an effective method for the arylation oftertiary alkoxides.

SUMMARY OF THE INVENTION

The present invention provides general and attractive routes to a widerange of aryl ethers. The methods provide several improvements overmethods known heretofore, namely, the efficient synthesis of aryl ethersunder mild conditions and in high yields. In particular, the method ofthe invention may be used in coupling reactions using tertiary alcohols.In other aspects of the invention, the invention provides a class oftransition metal complexes useful in the catalytic reactions of theinvention which were heretofore not known to be useful in thepreparation of aryl ethers.

In one aspect of the invention, an aryl ether compound is prepared byreacting an alcohol or its corresponding alkoxide salt with an aromaticcompound in the presence of a base and a catalyst selected from thegroup consisting of complexes of platinum, palladium and nickel. Thearomatic compound comprises an activated substituent, X, and theactivated substituent is a moiety such that its conjugate acid HX has apKa of less than 5.0. When the reaction takes place using an alkoxidesalt, a base may not be required.

In preferred embodiments, the reaction employs about 0.0001 to 20 mol %catalyst metal, preferably 0.05 to 5 mol % catalyst metal, and mostpreferably 1 to 3 mol % catalyst with respect to at least one of thealcohol and the aromatic compound. In other preferred embodiments, thereaction is carried out at a temperature in the range of about 50° C. toabout 120° C., and preferably in the range of about 65° to about 100° C.In other preferred embodiments, the aryl ether is obtained in greaterthan 45% yield and preferably in greater than 75% yield. The reaction issubstantially complete in less than about 12 hours, preferably in lessthan about 6 hours and most preferably in less than about 2 hours.

In preferred embodiments, the transition metal catalyst comprises apalladium complex and is preferably a catalyst complex selected from thegroup consisting of tris(dibenzylideneacetone) dipalladium, palladiumacetate and bis(dibenzylideneacetone) palladium. The catalyst complexmay comprise a supporting ligand. In preferred embodiments, thesupporting ligand is selected from the group consisting of alkyl andaryl derivatives of phosphines, bisphosphines, imines, amines, phenols,arsines, and hybrids thereof. In other preferred embodiments, thesupporting ligand is selected from the group consisting of(±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and separate enantiomersthereof; (±)-2,2'-bis(di-p-tolylphosphino)-1, 1'-binaphthyl and separateenantiomers thereof; 1-1'-bis(diphenylphosphino)ferrocene;1,3-bis(diphenylphosphino)propane; and 1,2-bis(diphenylphosphino)ethane.

In other embodiments, the alcohol and the aromatic compound are presentin substantially stoichiometric amounts. In yet other embodiments,either the alcohol or the aromatic compound is present in no greaterthan a two-fold excess relative to the limiting reagent and preferablyin no greater than about a 20% excess relative to the limiting reagent.In other preferred embodiments, no more than 4 equivalents andpreferably no more than 2 equivalents of base is present.

By "supporting ligand", as that term is used herein, it is meant acompound added to the reaction solution in an uncomplexed state, butwhich is capable of binding with the catalyst metal center. Althoughsuch interaction is possible, it is not required in order to observe thedesirable reaction products, yields and conditions according to thepresent invention. Alternatively, the supporting ligand may be complexedto the metal center to provide a pre-made catalyst complex comprisingthe metal and supporting ligand. The invention makes reference toseveral supporting ligands in an abbreviated form, where BINAP=(±)-2,2'-bis(diphenylphosphino)- 1,1'-binaphthyl (or separated enantiomers);Tol-BINAP=(±)-2,2'-bis-(di-p-tolylphosphino)-1, 1'-binaphthyl (orseparated enantiomers); dppf=1-1'-bis(diphenylphosphino)ferrocene;ppfa=(±)-N,N-dimethyl-1-[2-(diphenylphosphino)ferrocenyl]ethylamine (orseparated enantiomers);ppfe=(±)-(R)-1-[(S)-2-(diphenylphosphino)-ferrocenyl]ethyl methyl ether(or separated enantiomers); dppp=1,3-bis(diphenylphosphino)propane;dppb=1,2-bis(diphenylphosphino)benzene, anddppe=1,2-bis(diphenylphosphino)ethane.

By "functionalized" alcohol or aromatic, as that term is used herein, itis meant a compound containing both the alcohol (or aromatic) moiety andadditional functional groups which impart additional functionality orreactivity to the moiety, but which are not altered during the syntheticsequence of the invention.

BRIEF DESCRIPTION OF THE DRAWING

The FIGURE is a scheme illustrating possible reaction steps in thesynthesis of aryl ethers according to the method of the invention.

DESCRIPTION OF THE PREFERRED EMBODIMENT

A wide range of alcohols (and alkoxide salts) have been shown to reactwith aromatic compounds containing an activated substituent (a "good"leaving group) to obtain the corresponding aryl ether. The generalreaction is set forth in eq. 1 and is carried out in the presence of abase and a transition metal catalyst complex. ##STR1##

According to eq. 1, an alcohol 1 is reacted with an aromatic compound 2having an activated substituent, X, to form an aryl ether 3 in thepresence of a catalytic amount of a transition metal catalyst complexand a base. The reaction proceeds at mild temperatures in the presenceof a transition metal complex (with or without a supporting ligand) andsuitable base. The reaction may be either an intermolecular orintramolecular reaction.

The reaction most likely proceeds via oxidative-addition of the aromaticcompound 2 to a zero-valent catalyst metal center, substitution of X bythe alcohol 1 at the metal center, followed by reductive-elimination togenerate the aryl ether 3. The base presumably promotes formation of anoxygen-metal bond, in which the metal is the metal center of thecatalyst, presumably by facilitating proton abstraction from the alcoholhydrogen.

The aromatic compound 2 may be any aromatic compound having a goodleaving group. By way of example, the aromatic compound may be selectedfrom the group consisting of phenyl and phenyl derivatives,heteroaromatic compounds, polycyclic aromatic and heteroaromaticcompounds, and functionalized derivatives thereof. Suitable aromaticcompounds derived from simple aromatic rings and heteroaromatic rings,include but are not limited to, pyridine, imidizole, quinoline, furan,pyrrole, thiophene, and the like. Suitable aromatic compounds derivedfrom fused ring systems, include but are not limited to naphthalene,anthracene, tetralin, indole and the like.

The aromatic compound may have the formula (Z)_(n) ArX, where X is anactivated substituent. An activated substituent, X, is characterized asbeing a good leaving group which readily lends itself to substitution.For the purposes of the present invention, an activated substituent isthat moiety whose conjugate acid, HX, has a pKa of less than 5.0.Suitable activated substituents include, by way of example only, halidessuch as chloride, bromide and iodide, triflate, mesylate, tosylate anddiazonium. An additional leaving group may be SR, where R=aryl or alkyl.

Z is an optional substituent on the aromatic ring. Z may be a functionalgroup which imparts additional functionality or reactivity to thearomatic substrate, but which is not altered during the syntheticsequence of the invention. By way of example only, suitable Z includealkyl, aryl, acyl, heteroaryl, amino, carboxylic ester, carboxylic acid,hydrogen group, ether, thioether, amide, carboxamide, nitro, phosphonicacid, hydroxyl, sulfonic acid, halide, pseudohalide groups, andsubstituted derivatives thereof, and n is in the range of 0 to 5. Inparticular, the reaction has been found compatible with acetals, amidesand silyl ethers as functional groups. For fused rings, where the numberof substitution sites on the aromatic ring increases, n may be adjustedappropriately. In addition, the above mentioned moieties may becovalently linked to an alcohol moiety in intramolecular reactions.

The alcohol is selected to provide the desired reaction product. Ingeneral, the alcohol may be any alcohol such as, but not limited to,alkyl alcohols, including primary, secondary and tertiary alcohols, andphenols. The alcohol may be functionalized. The alcohol may be selectedfrom a wide variety of structural types, including but not limited to,acyclic, cyclic or heterocyclic compounds, fused ring compounds orphenol derivatives. The aromatic compound and the alcohol may beincluded as moieties of a single molecule, whereby the arylationreaction proceeds as an intramolecular reaction. Alternatively, thecorresponding alkoxide salt, e.g., NaOR, LiOR, KOR, etc., may beprepared and used in place of the alcohol in eq. 1. When thecorresponding alkoxide is used in the reaction, an additional base maynot be required.

In preferred embodiments of the invention, there is no need to use largeexcesses of either reactant--alcohol or aromatic compound. The reactionproceeds quickly and in high yields to the product aryl ether usingsubstantially stoichiometric amount of reagents. Thus, the alcohol maybe present in no greater than a two-fold excess and preferably in nogreater than a 20% excess relative to the aromatic compound.Alternatively, the aromatic compound may be present in no greater than atwo-fold excess and preferably in no greater than a 20% excess relativeto the alcohol.

Suitable transition metal catalysts include soluble complexes ofplatinum, palladium and nickel. Nickel and palladium are particularlypreferred and palladium is most preferred. A zero-valent metal center ispresumed to participate in the catalytic carbon-oxygen bond formingsequence. Thus, the metal center is desirably in the zero-valent stateor is capable of being reduced to metal(0). Suitable soluble palladiumcomplexes include, but are not limited to, tris(dibenzylideneacetone)dipalladium [Pd₂ (dba)₃ ], bis(dibenzylideneacetone) palladium [Pd(dba)₂] and palladium acetate. Alternatively, particularly for nickelcatalysts, the active species for the-oxidative-addition step may be inthe metal (+1) oxidative-addition state.

The catalyst may also be a complex comprising a bound supporting ligand,that is, a metal-supporting ligand complex. This catalyst complex mayinclude additional ligands as is necessary to obtain a stable complex.By way of example, PdCl₂ (BINAP) may be prepared in a separate step andused as the catalyst complex set forth in eq. 1.

The active form of the transition metal catalyst is not wellcharacterized. Therefore, it is contemplated that the "transition metalcatalyst" of the present invention, as that term is used herein, shallinclude any transition metal catalyst and/or catalyst precursor as it isintroduced into the reaction vessel and which is, if necessary,converted in situ into the active phase, as well as the active form ofthe catalyst which participates in the reaction.

In preferred embodiments, the transition metal catalyst complex ispresent in the range of 0.0001 to 20 mol %, and preferably 0.05 to 5 mol%, and most preferably 1-3 mol %, with respect to the limiting reagent,which may be either the aromatic compound or the alcohol (or alkoxide)or both, depending upon which reagent is in stoichiometric excess. Inthe instance where the molecular formula of the catalyst complexincludes more than one metal, the amount of the catalyst complex used inthe reaction may be adjusted accordingly. By way of example, Pd₂ (dba)₃has two metal centers; and thus the molar amount of Pd₂ (dba)₃ used inthe reaction may be halved without sacrifice to catalytic activity.

Additionally, heterogeneous catalysts containing forms of these elementsare also suitable catalysts for any of the transition metal catalyzedreactions of the present invention. Catalysts containing palladium andnickel are preferred. It is expected that these catalysts will performsimilarly because they are known to undergo similar reactions, namelyoxidative-addition reactions and reductive-elimination reactions, whichare thought to be involved in the formation of the aryl ethers of thepresent invention. However, the different ligands are thought to modifythe catalyst performance by, for example, modifying reactivity andpreventing undesirable side reactions.

The catalyst complex is usually used in combination with supportingligands. The supporting ligand may be added to the reaction solution asa separate compound or it may be complexed to the metal center to form ametal-supporting ligand complex prior to its introduction into thereaction solution. Supporting ligands are compounds added to thereaction solution which are capable of binding to the catalyst metalcenter, although an actual metal-supporting ligand complex has not beenidentified in each and every synthesis. In some preferred embodiments,the supporting ligand is a chelating ligand. Although not bound by anytheory of operation, it is hypothesized that the supporting ligandsprevent unwanted side reactions as well as enhancing the rate andefficiency of the desired process. Additionally, they often aid inkeeping the metal catalyst soluble. Although the present invention doesnot require the formation of a metal-supporting ligand complex, suchcomplexes have been shown to be consistent with the postulate that theyare intermediates in these reactions and it has been observed theselection of the supporting ligand has an affect on the course of thereaction.

The supporting ligand is present in the range of 0.0001 to 40 mol %relative to the limiting reagent, i.e., alcohol or aromatic compound.The ratio of the supporting ligand to catalyst complex is typically inthe range of about 1 to 20, and preferably in the range of about 1 to 4and most preferably about 2.4. These ratios are based upon a singlemetal complex and a single binding site ligand. In instances where theligand contains additional binding sites (i.e., a chelating ligand) orthe catalyst contains more than one metal, the ratio is adjustedaccordingly. By way of example, the supporting ligand BINAP contains twocoordinating phosphorus atoms and thus the ratio of BINAP to catalyst isadjusted downward to about 1 to 10, preferably about 1 to 2 and mostpreferably about 1.2. Conversely, Pd₂ (dba)₃ contains two palladiummetal centers and the ratio of ligand to Pd₂ (dba)₃ is adjusted upwardto 1 to 40, preferably 1 to 8 and most preferably about 4.8.

Suitable supporting ligands, such as by way of example only, includealkyl and aryl derivatives of phosphines, bisphosphines, imines, amines,arsines, phenols and hybrids thereof, including hybrids of phosphineswith amines and or ethers. Suitable phosphine ligands includeP(o-tolyl)₃. Bis(phosphine) ligands are particularly preferred chelatingsupporting ligands. Suitable bis(phosphine) compounds include but are inno way limited to (±)-2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl (andseparate enantiomers), (±)-2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl (and separate enantiomers),1-l'-bis(diphenylphosphino)ferrocene, 1,3-bis(diphenylphosphino)propane;1 ,2-bis(diphenylphosphino)benzene, and 1,2-bis(diphenylphosphino)ethane. Hybrid chelating ligands such as(±)-N,N-dimethyl-1-[2-(diphenylphosphino) ferrocenyl]ethylamine (andseparate enantiomers), and(±)-(R)-1-[(S)-2-(diphenylphosphino)-ferrocenyl]ethyl methyl ether (andseparate enantiomers) are also within the scope of the invention.

In general, a variety of bases may be used in practice of the presentinvention. The base is desirably capable of extraction of a proton topromote metal-alkoxide formation. It has not been determined ifdeprotonation occurs prior to or after oxygen coordination. The base mayoptionally be sterically hindered to discourage metal coordination ofthe base in those circumstances where such coordination is possible,i.e., alkali metal alkoxides. By way of example only, suitable basesinclude NaH, LiH, KH, K₂ CO₃, Na₂ CO₃, Tl₂ CO₃, Cs₂ CO₃, K(OtBu),Li(OtBu), Na(OtBu) K(OPh), Na(OPh), triethylamine or mixtures thereof.NaH, Na(OtBu) and K₂ CO₃ have been found useful in a wide variety ofaryl ether bond forming reactions. Base is used in approximatelystoichiometric proportions in reaction using alcohol. The presentinvention has demonstrated that there is no need for large excesses ofbase in order to obtain good yields of aryl ether under mild reactionconditions. No more than four equivalents and preferably no more thantwo equivalents are needed. Further, in reactions using thecorresponding alkoxide as the reagent, there may be no need foradditional base.

The reaction proceeds at mild temperatures to give high yields of theproduct aryl it ether. Thus, yields of greater than 45%, preferablygreater than 75% and even more preferably greater than 80% may beobtained by reaction at mild temperatures according to the invention.The reaction may be carried out at temperature less than 120° C., andpreferably in the range of 50-120° C. In one preferred embodiment, thereaction is carried out at a temperature in the range of 80-100° C.

While not being bound by any particular mode of operation, it ishypothesized that the mechanism of the Pd-catalyzed synthesis of arylethers most likely proceeds via a pathway roughly similar to thatsuggested for a palladium-catalyzed arylamination reaction. The Figurepresents a proposed reaction pathway for the synthesis of a heterocyclicether via an intramolecular reaction. Phosphine ligands have beenomitted for clarity. With reference to the Figure, oxidative addition ofthe Pd(0)L_(n) complex with the aryl halide affords the Pd(II)organometallic complex intermediate A. In the presence of a suitablebase, reaction of the alcohol (or alkoxide) moiety could affordmetallacycle C, which would then undergo reductive elimination to yieldthe oxygen heterocycle. The reaction sequence is expected to be the samefor intermolecular reactions.

The invention may be understood with reference to the followingexamples, which are presented for illustrative purposes only and whichare non-limiting. Alcohols and aromatic compounds for intermolecularreactions were all commercially available. Substrates used inintramolecular reactions were prepared using standard synthetic organicmethods in about 3-5 synthetic steps. Palladium catalysts were allcommercially available.

Example 1-11. Examples 1-11 demonstrate the versatility of the arylether synthetic route of the invention. A variety of substitutedaromatic compounds with attached alcohol moieties were subjected topalladium-catalyzed cross coupling to afford variously substitutedheterocyclic ethers. The starting aromatic compounds and alcohols arereported in Table 1. The reactions were carried out as described in thelegend.

As shown in Table 1, five, six and seven-membered heterocycles wereobtained in good yields from the corresponding aryl halide. In addition,a number of functional groups were found compatible with the reactionconditions including acetals (Example 3), silyl ethers (Example 4), andamides (Example 7). Reactions performed using method A weresignificantly slower (24-36 h) than reactions performed using method B(1-6 h), however, the reactions using method A were somewhat cleaner.Cyclization of the aryl iodide substrate (Example 2) was extremely slowin toluene, but in 1,4-dioxane, complete conversion occurred in 24-36 h.Two equivalents of ligand relative to palladium (P:Pd=4) and twoequivalents of base relative to substrate were used to achievereasonable yields in the cyclization reactions of Example 11 containinga secondary alcohol. Observed side products included dehalogenation ofthe aryl halides and in the case of substrates containing secondaryalcohols, along with the oxidation of the alcohol to a ketone.

Example 12. This example demonstrates the palladium-catalyzedintermolecular synthesis of the aryl ether, 4-t-butoxybenzonitrile.

A Schlenk tube was charged with Na(OtBu) (97 mg, 1.00 mmol), Pd(OAc)₂(5.6 mg, 0.025 mmol),(R)-(+)-2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl(Tol-BINAP) (20.4mg, 0.030 mmol), 4-bromobenzonitrile (91 mg, 0.50 mmol), and toluene (3mL).

                                      TABLE 1                                     __________________________________________________________________________    Pd-Catalyzed Synthesis of Cyclic Aryl Ethers.                                 Entry                                                                             Substrate           Method.sup.a                                                                       Product           Yield (%).sup.b                __________________________________________________________________________      1                                                                                                                            A TR2##                                                                       89 R3##                         - 2                                                                                                                         A TR4##                                                                       60 R5##                         - 3                                                                                                                         A TR6##                                                                       93 R7##                         - 4                                                                                                                         A TR8##                                                                       90 R9##                         - 5                                                                                                                         A TR10##                                                                      65 R11##                        - 6                                                                                                                         A TR12##                                                                      73 R13##                        - 7                                                                                                                         A TR14##                                                                      66 R15##                        - 8                                                                                                                         B TR16##                                                                      69 R17##                        - 9                                                                                                                         B TR18##                                                                      64 R19##                        - 10                                                                                                                        B TR20##                                                                      73 R21##                        - 11                                                                                                                        C TR22##                                                                      66TR23##                     __________________________________________________________________________     .sup.a Method A: 5 mol % Pd(OAc).sub.2, 6 mol % TolBINAP, 1.2 equiv of        K.sub.2 CO.sub.3 in toluene at 100° C. Method B: 3 mol %               Pd(OAc).sub.2, 3.6 mol % DPPF, 1.2 equiv NaOtBu in toluene at 80°      C. Method C: 5 mol % Pd(OAc).sub.2, 10 mol % DPPF, 2.0 equiv NaOtBu in        toluene at 90° C.                                                      .sup.b Yields refer to average isolated yields of two or more runs.           .sup.c Reaction was performed in 1,4dioxane.                             

The mixture was heated at 100° C. for 30 h under an atmosphere of argon.The mixture was cooled to room temperature and diethyl ether (20 mL) andwater (20 mL) were added. The organic layer was separated, washed withbrine (20 mL), dried over anhydrous MgSO₄, and concentrated in vacuo.The crude product was purified by flash chromatography on silica gel(19/1 hexane/ethyl acetate) to afford 4-t-butoxybenzonitrile as a yellowoil (39 mg, 45% yield).

Example 13. This example demonstrates the palladium-catalyzedintermolecular synthesis of the aryl ether, 4-t-butylphenyl t-butylether.

An oven dried Schlenk equipped with a teflon coated stir bar was chargedwith Na(Ot-Bu) (97 mg, 1.00 mmol), Pd(OAc)₂ (5.6 mg, 0.025 mmol), andTol-BINAP (20.4 mg, 0.030 mmol). The Schlenk was evacuated, back-filledwith argon, and charged with toluene (3 mL) and 4-t-butyl bromobenzene(87 μL, 0.50 mmol). The mixture was heated at 100° C. for 40 h at whichtime the mixture was cooled to room temperature and diethyl ether (20mL) and water (20 mL) were added. The organic layer was separated,washed with brine (20 mL), dried over anhydrous MgSO₄, and concentratedin vacuo. The crude product was purified by flash chromatography onsilica gel (99/1 hexane/ethyl acetate) to afford 4-t-butylphenyl t-butylether as a yellow oil (59 mg, 53% yield).

Example 14. This example demonstrates the palladium-catalyzedintermolecular synthesis of the aryl ether, 4-benzonitrile cyclopentylether.

A Schlenk tube was charged with NaH (80.0 mg, 60% dispersion in mineraloil, 2.00 mmol), cyclopentanol (182 μL, 2.00 mmol), and toluene (2.5mL). The mixture was heated at 70° C. for 30 minutes under an atmosphereof argon followed by the addition of Pd(OAc)₂ (6.7 mg, 0.030 mmol),(R)-(+)-2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl (Tol-BINAP) (27.2mg, 0.040 mmol), 4-bromobenzonitrile (182 mg, 1.00 mmol), and toluene(2.5 mL). The mixture was heated at 100° C. for 1.5 h at which timediethyl ether (30 mL) and water (30 mL) were added at room temperature.The organic layer was separated, washed with brine (20 mL), dried overanhydrous MgSO₄, and concentrated in vacuo. The crude product waspurified by flash chromatography on silica gel (19/1 hexane/ethylacetate) to afford 4-benzonitrile cyclopentyl ether as a colorless oil(140 mg, 75% yield).

Example 15. This example demonstrates the palladium-catalyzedintermolecular synthesis of the aryl ether, 4-benzonitrile isopropylether.

An oven dried Schlenk tube equipped with a teflon coated stir bar wascharged with NaH (60% dispersion in mineral oil, 40 mg, 1.00 mmol),placed under vacuum, and back-filled with argon. To this was added2-propanol (46 μL, 0.60 mmol) and toluene (2 mL). The mixture was heatedat 50° C. for 15 min at which time the 4-bromobenzonitrile (91 mg, 0.50mmol), Pd₂ (dba)₃ (6.9 mg, 0.0075 mmol),(R)-(+)-2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl (Tol-BINAP) (12.2mg, 0.018 mmol), and 1 mL of toluene were added. The mixture was heatedto 50° C. while under an atmosphere of argon. After 22 h, water (50 mL)and diethyl ether (50 mL) were added and the aqueous layer separated andextracted with diethyl ether (50 mL). The organics were combined, washedwith brine (50 mL) and dried over anhydrous MgSO₄. The crude product waspurified by flash chromatography on silica gel (19:1 hexane/ethylacetate) to afford 4-benzonitrile isopropyl ether (65 mg, 80% yield) asa white solid.

Example 16. This example demonstrates the palladium-catalyzedintermolecular synthesis of the aryl ether, 1-naphthyl cyclohexyl ether.

An oven dried Schlenk tube equipped with a teflon coated stir bar wascharged with NaH (40 mg, 1.50 mmol), toluene (2 mL) and cyclohexanol (94μL, 0.90 mmol). The mixture was heated to 70° C. for 10 min under anatmosphere of argon. To this was added 1-bromonaphthalene (104 μL, 0.75mmol), Pd₂ (dba)₃ (10.3 mg, 0.0113 mmol),(R)-(+)-2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl(Tol-BINAP) (18.3mg, 0.027 mmol), and 2 mL of toluene. The mixture was heated to 70° C.for 20 h at which time water (60 mL) and diethyl ether (60 mL) wereadded. The aqueous layer was separated and extracted with diethyl ether(60 mL). The organics were combined, washed with brine (60 mL) and driedover anhydrous MgSO₄. The drying agent was removed by filtration and themother liquor concentrated in vacuo. The crude product was purified byflash chromatography on silica gel (50:1 hexanes:ethyl acetate) toafford 1-naphthyl cyclohexyl ether (101 mg, 60% yield) as a colorlessoil.

Example 17. This example demonstrates the palladium-catalyzedintermolecular synthesis of the aryl ether,3-pentyl-(4-trifluoromethylphenyl) ether.

An oven dried Schlenk tube equipped with a teflon coated stir bar wascharged with NaH (60% dispersion in mineral oil, 60 mg, 1.50 mmol),placed under vacuum and back-filled with argon. To this was addedtoluene (2 mL) and 3-pentanol (98 μL, 0.90 mmol). The mixture was heatedat 70° C. for 10 min at which time 4-bromobenzotrifluoride (105 μL, 0.75mmol), Pd₂ (dba)₃ (10.3 mg, 0.0113 mmol),(R)-(+)-2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl (Tol-BINAP) (18.3mg, 0.027 mmol), and 1 mL of toluene were added. The mixture was heatedto 70° C. for 18 h at which time diethyl ether (60 mL) and water (60 mL)were added. The aqueous layer was separated and extracted with diethylether (60 mL). The organics were combined, washed with brine (60 mL) anddried over MgSO₄. The drying agent was removed by filtration and themother liquor concentrated in vacuo. The crude product was purified byflash chromatography on silica gel (19:1 hexanes:ethyl acetate) toafford 3-pentyl-(4-trifluoromethylphenyl) ether (114 mg, 54% yield) as acolorless oil.

Example 18. This example demonstrates the palladium-catalyzedintermolecular synthesis of the aryl ether, 9-anthryl cyclopentyl ether.

An oven dried Schlenk tube equipped with a teflon coated stir bar wascharged with NaH (60% dispersion in mineral oil, 60 mg, 1.50 mmol),placed under vacuum and back-filled with argon. To this was addedtoluene (2 mL) and cyclopentanol (109 μL, 0.90 mmol). The mixture washeated at 70° C. for 15 min at which time 9-bromoanthracene (193 μL,0.75 mmol), Pd₂ (dba)₃ (10.3 mg, 0.0113 mmol),(R)-(+)-2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl (Tol-BINAP) (18.3mg, 0.027 mmol), and 2 mL of toluene were added. The mixture was heatedat 100° C. under an atmosphere of argon. After 20 hours diethyl ether(30 mL) and brine (30 mL) were added. The organic layer was separatedand dried over anhydrous MgSO₄. The drying agent was removed byfiltration and the mother liquor concentrated in vacuo. The crudeproduct was purified by flash chromatography on silica gel (99:1hexanes:ethyl acetate) to afford 9-anthryl cyclopentyl ether (135 mg,68% yield) as a yellow solid

Example 19. This example demonstrates the palladium-catalyzedintermolecular synthesis of the aryl ether, 4-benzonitrile benzyl ether.

An oven dried Schlenk tube equipped with a teflon coated stir bar wascharged with NaH (60% dispersion in mineral oil, 60 mg, 1.50 mmol),placed under vacuum and back-filled with argon. To this was addedtoluene (2 mL) and benzyl alcohol (93 μL, 0.90 mmol). The mixture washeated at 70° C. for 10 min at which time 4-bromobenzonitrile (136 μL,0.75 mmol), Pd₂ (dba)₃ (10.3 mg, 0.0113 mnmol),(R)-(+)-2,2'-bis(di-p-tolylphosphino)- 1, 1'-binaphthyl (Tol-BINAP)(18.3 mg, 0.027 mmol), and 1 mL of toluene were added. The mixture washeated at 70° C. under an atmosphere of argon. After 14 hours diethylether (50 mL) and water (50 mL) were added. The aqueous layer wasseparated and extracted with diethyl ether (50 mL). The organics werecombined, washed with brine (50 mL), and dried over MgSO₄. The dryingagent was removed by filtration and the mother liquor concentrated invacuo. The crude product was purified by flash chromatography on silicagel (19:1 hexanes:ethyl acetate) to afford 4-benzonitrile benzyl ether(113 mg, 72% yield) as a white solid.

Example 20. This example demonstrates the palladium-catalyzedintermolecular synthesis of the aryl ether, 4-benzonitrile methyl ether.

An oven dried Schlenk tube equipped with a teflon coated stir bar wascharged with NaH (60% dispersion in mineral oil, 60 mg, 1.50 mmol),placed under vacuum and back-filled with argon. To this was addedtoluene (2 mL) and methyl alcohol (87 μL, 0.90 mmol). Ihe mixture washeated at 70° C. for 10 min at which time 4-bromobenzonitrile (136 μL,0.75 mmol), Pd₂ (dba)₃ (10.3 mg, 0.0113 mmol),(R)-(+)-2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl (Tol-BINAP) (18.3mg, 0.027 mmol), and 1 mL of toluene were added. The mixture was heatedat 70° C. under an atmosphere of argon. After 20 hours diethyl ether (50mL) and water (50 mL) were added. The aqueous layer was separated andextracted with diethyl ether (50 mL). The organics were combined, washedwith brine (50 mL), and dried over MgSO₄. The drying agent was removedby filtration and the mother liquor concentrated in vacuo. The crudeproduct was purified by flash chromatography on silica gel (19:1hexanes:ethyl acetate) to afford 4-benzonitrile methyl ether (77 mg, 77%yield) as a white solid.

Other embodiments of the invention will be apparent to the skilled inthe art from a consideration of the specification or practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only with the true scope and spiritof the invention being indicated by the following claims.

What is claimed is:
 1. A method of preparing an aryl ether, representedby the following reaction: ##STR24## wherein R' is selected from thegroup consisting of optionally substituted alkyl, heteroalkyl, aryl, andheteroaryl;Ar represents an optionally substituted aromatic orheteroaromatic group; catalyst is a complex comprising a transitionmetal, selected from the group consisting of platinum, palladium, andnickel, and a supporting ligand; base is selected from the groupconsisting of hydrides, carbonates, alkoxides, aryloxides, and amides;and X is selected from the group consisting of halides, sulfonates,diazonium and alkylthio.
 2. A method of preparing an aryl ether,represented by the following reaction: ##STR25## wherein R' is selectedfrom the group consisting of optionally substituted alkyl, heteroalkyl,aryl, and heteroaryl;Ar represents an optionally substituted aromatic orheteroaromatic group; catalyst is a complex comprising a transitionmetal, selected from the group consisting of platinum, palladium, andnickel, and a supporting ligand; M represents a cation; and X isselected from the group consisting of halides, sulfonates, diazonium andalkylthio.
 3. The method of claim 1 or 2, wherein X is selected from thegroup consisting of chloride, bromide, iodide, triflate, mesylate andtosylate.
 4. The method of claim 1 or 2, wherein X is bromide.
 5. Themethod of claim 1 or 2, wherein Ar represents an optionally substitutedmonocyclic aromatic or heteroaromatic group.
 6. The method of claim 1 or2, wherein catalyst is a complex comprising palladium and a supportingligand.
 7. The method of claim 1 or 2, wherein the supporting ligand isa chelating bis(phosphine).
 8. The method of claim 1 or 2, wherein R' isan optionally substituted alkyl.
 9. The method of claim 1 or 2, whereinthe reaction is intramolecular.
 10. The method of claim 1 or 2, whereinX is selected from the group consisting of chloride, bromide, iodide,triflate, mesylate and tosylate; and catalyst is a complex comprisingpalladium and a supporting ligand.
 11. The method of claim 10, whereinthe supporting ligand is a chelating bis(phosphine).
 12. The method ofclaim 1 or 2, wherein X is bromide; and catalyst is a complex comprisingpalladium and a supporting ligand.
 13. The method of claim 12, whereinthe supporting ligand is a chelating bis(phosphine).
 14. The method ofclaim 1, wherein base is selected from the group consisting of sodiumhydride, lithium hydride, potassium hydride, sodium carbonate, potassiumcarbonate, cesium carbonate, thallium carbonate, lithium tert-butoxide,sodium tert-butoxide, potassium tert-butoxide, sodium phenoxide andpotassium phenoxide.
 15. The method of claim 1, wherein base is selectedfrom the group consisting of sodium hydride, potassium carbonate andsodium tert-butoxide.
 16. The method of claim 14 or 15, wherein X isselected from the group consisting of chloride, bromide, iodide,triflate, mesylate and tosylate.
 17. The method of claim 14 or 15,wherein X is bromide.
 18. The method of claim 14 or 15, wherein catalystis a complex comprising palladium and a supporting ligand.
 19. Themethod of claim 2, wherein M represents lithium, sodium, potassium,cesium, thallium or ammonium.
 20. The method of claim 2, wherein Mrepresents sodium or potassium.
 21. The method of claim 19 or 20,wherein X is selected from the group consisting of chloride, bromide,iodide, triflate, mesylate and tosylate.
 22. The method of claim 19 or20, wherein X is bromide.
 23. The method of claim 21, wherein catalystis a complex comprising palladium and a supporting ligand.
 24. Themethod of claim 22, wherein catalyst is a complex comprising palladiumand a supporting ligand.